Tetrazolyl substituted thioethers, pharmaceutical compositions and anti-allergic use thereof

ABSTRACT

The present invention provides compounds of the general formula: ##STR1## wherein Ar is a phenyl radical optionally substituted by alkyl, alkenyl, alkoxy, alkylthio, alkanoyl, hydroxyl, hydroxyalkyl, carboxyl, alkoxycarbonyl, carbamoyl, nitro, amino or halogen, A is a straight-chained or branched, saturated or unsaturated C 1  -C 8  aliphatic hydrocarbon radical which is optionally substituted by a hydroxyl group, n is 0, 1 or 2, B is a straight-chained or branched, saturated or unsaturated C 1  -C 8  -aliphatic hydrocarbon radical and R is 5-(1H)-tetrazolyl, --CO--NH-tetrazolyl, ##STR2## Cn, SCN, OH, halogen, 5-(1H)-tetrazolylthio, ##STR3## or CO--O--NH--R 1 , wherein R 1  is a hydrogen atom, an alkyl radical optionally substituted by cycloalkyl or an alkenyl, cycloalkyl, aralkyl or aryl radical, wherein the aromatic moiety can be substituted by alkyl, alkenyl, alkoxy, alkylthio, alkanoyl, hydroxyl, hydroxyalkyl, carboxyl, alkoxycarbonyl, carbamoyl, nitro, amino or halogen; and the pharmacologically acceptable salts thereof. The present invention also provides processes for preparing these compounds and pharmaceutical compositions containing them for combating allergic diseases.

This is a division application of application Ser. No. 011,096, filedFeb. 5, 1987, now U.S. Pat. No. 4,906,666.

The present invention is concerned with new thioethers, processes forthe preparation thereof and pharmaceutical compositions containing thesecompounds.

Analogous compounds are known from Federal Republic of Germany PatentSpecification No. 33 24 916 and from European Patent Specification No.0,131,221. However, in contradistinction to these known compounds, thenew compounds according to the present invention have a stronger degreeof action in the same dosage range.

In the case of oral and parenteral administration, the compoundsaccording to the present invention inhibit anaphylactic andanaphylactoid reactions such as can be initiated, for example, onsensitised guinea pigs by allergen provocation. Moreover, they have ananti-inflammatory effect. Therefore, they are useful for combatingallergic diseases, for example allergic asthma.

The new thioethers according to the present invention are compounds ofthe general formula: ##STR4## wherein Ar is a phenyl radical optionallysubstituted by alkyl, alkenyl, alkoxy, alkylthio, alkanoyl, hydroxyl,hydroxyalkyl, carboxyl, alkoxycarbonyl, carbamoyl, nitro, amino orhalogen, A is a straight-chained or branched, saturated or unsaturatedC₁ -C₈ aliphatic hydrocarbon radical which is optionally substituted bya hydroxyl group, n is 0, 1 or 2, B is a straight-chained or branched,saturated or unsaturated C₁ -C₈ aliphatic hydrocarbon radical and R is5-(1H)-tetrazolyl, -CO-NH-tetrazolyl, ##STR5## CN, SCN, OH, halogen,5-(1H)-tetrazolylthio, ##STR6## or --CO--O--NH--R₁, wherein R₁ ishydrogen atom, an alkyl radical optionally substituted by cycloalkyl oran alkenyl, cycloalkyl, aralkyl or aryl radical, wherein the aromaticmoiety can be substituted by alkyl, alkenyl, alkoxy, alkylthio,alkanoyl, hydroxyl, hydroxyalkyl, carboxyl, alkoxycarbonyl, carbamoyl,nitro, amino or halogen; as well as the pharmacologically acceptablesalts thereof.

The above-mentioned alkyl radicals as such or as parts of other radicalscontain up to 6 carbon atoms and can be straight-chained or branched.

In particular, alkyl can be a methyl, ethyl, propyl or butyl radical,alkoxy can be a methoxy or ethoxy radical, alkylthio can be anmethylthio radical, hydroxyalkyl can be a hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxybutyl, hydroxypentyl or hydroxyhexyl radical, thehydroxyl substituent being at any desired position of the alkyl chain,and alkoxycarbonyl can be a methoxycarbonyl or ethoxycarbonyl radical.

Alkanoyl radicals preferably contain up to 4 carbon atoms, for exampleformyl, acetyl or propionyl.

Cycloalkyl radicals preferably contain 3 to 7 carbon atoms, especiallycyclopentyl and cyclohexyl.

The aralkyl radical is preferably a benzyl or phenethyl radical.

The group A represents a C₁ -C₈ aliphatic hydrocarbon radical, thosewith 2 to 5 carbon atoms being preferred, for example ethylene,propylene and butylene, in which case the propylene radical inparticular can contain a hydroxyl substituent. Unsaturated radicals arepreferably --CH₂ --CH═CH--CH₂ -- or --CH₂ --C≡C--CH₂ --.

The group B is a C₁ -C₈ aliphatic hydrocarbon radical, preferablymethylene, ethylene, propylene, butylene or pentylene. A branchedalkylene radical is preferably the --C(CH₃) radical. Unsaturatedradicals are, in particular, --CH₂ --CH═CH-- and --CH₂ --C≡C--.

The alkenyl radical contains 2 to 6 carbon atoms, the allyl radicalbeing preferred.

The halogen atoms are fluorine, chlorine or bromine.

Preferred compounds are those in which Ar is substituted one, two orthree times, Ar being a methoxyphenyl, pentylphenyl, hydroxyhexylphenyl,dichlorophenyl, 4-acetyl-3-hydroxy-2-propylphenyl or4-acetyl-2-allyl-3-hydroxyphenyl radical or R isN-hydroxy-N-methylaminocarbonyl, N-ethyl-N-hydroxyaminocarbonyl,N-cyclohexyl-N-hydroxyaminocarbonyl, 5-tetrazolylaminocarbonyl,5-tetrazolyl, 5-tetrazolylthio, N-hydroxyaminocarbonyl, hydroxyl, halo,cyano or thiocyanato.

Apart from the compounds mentioned hereinafter in the specific Examples,the present invention also includes all compounds which display everypossible combination of the substituents mentioned in the Examples.

The present invention also provides pharmaceutical compositionscontaining at least one compound of general formula (I) and is alsoconcerned with the use of such compounds of general formula (I) for thepreparation of such compositions.

The present invention also provides a process for the preparation ofcompounds of general formula (I), wherein either

a) a compound of the general formula :

    Ar--O--A--X                                                (II)

is reacted with a compound of the general formula:

    Y--B--G                                                    (III)

in which Ar, A and B have the same meanings as above, one of the symbolsX and Y represents an --SH group and the other a reactive residue and Ghas the same meaning as R above or is a hydroxyl group; or

b) a compound of the general formula:

    Ar--O--A--S--B--COOH                                       (IV),

in which Ar, A and B have the same meanings as above, or a reactivederivative thereof, for example a carboxylic acid halide, carboxylicacid ester or a mixed carboxylic acid anhydride, is reacted with5-amino-(1H)-tetrazole or with a compound of the general formula:

    HO--NH--R.sub.1                                            (V),

in which R₁ has the same meaning as above, or with an O-silylatedderivative thereof;

whereafter, if desired, when G is a hydroxyl group, this is firstconverted, for example, into a reactive derivative, such as a halide,mesylate or tosylate, and then converted into a radical R, a radical Ris optionally converted into a different radical R, the sulphur atom isoptionally oxidised and the reaction product obtained is, if desired,converted into a pharmacologically acceptable salt.

Examples of reactive residues X and Y in compounds (II) and (III)include chlorine, bromine, mesyloxy and tosyloxy. Compounds of thegeneral formulae (II) and (III), in which Y is an --SH group, can beused as such or can be liberated in situ from an appropriate precursor,for example an S-alkylated 3-thio-1,2-benzisothiazole-1,1-dioxide or anS-alkylated isothiuronium salt.

Conversion of a radical R into a different radical R as definedhereinbefore can take place, for example, by reacting a compound ofgeneral formula (I), in which R is a cyano or thiocyanato group, withhydrazoic acid or with an alkali metal azide and a proton-providingsubstance, for example ammonium chloride or with a compound of generalformula (V).

The starting materials of general formulae (III) and (V) are eitherknown from the literature or can be prepared analogously to processesknown from the literature.

The preparation of compounds of general formulae (II) and (IV) is knownfrom European Patent Specification No. 0,131,221.

The process according to the present invention is carried out, forexample, by first reacting a compound of general formula (II), in whichX is a reactive residue, with a derivative of3-thio-1,2-benzisothiazole-1,1-dioxide which carries a -B-G radical onthe sulphur atom, in the presence of an equimolar amount of a secondaryamine, the reaction product obtained then being isolated.

The reaction is preferably carried out in a polar, aprotic solvent, forexample acetonitrile, in the presence of a tertiary amine.

If desired, the reaction product obtained can be reacted in a polar,aprotic solvent with an alkali metal azide or ammonium azide.

According to another variant of the process, a compound of generalformula (II) in which X is an --SH group, is alkylated with a compoundof general formula (III), in which Y is a reactive residue.

When G is a hydroxyl group, the product obtained by reaction with acompound of general formula (II) can be converted, for example, byreaction with triphenylphosphine and a tetrahalomethane in a halogenatedhydrocarbon, into a halide from which, by reaction in a polar, aproticsolvent, for example acetone, with an alkali metal cyanide or alkalimetal thiocyanate there is obtained a compound of general formula (I).

An oxidation of the sulphur atom in compounds of general formula (I) canbe carried out, for example, by oxidising according to known methods,for example with oxygen, hydrogen peroxide, tert.-butyl hydroperoxide oran organic per acid, in a solvent, such as dichloromethane, acetone oracetic acid, to give the corresponding sulphoxide or sulphone.

Especially preferred pharmacologically acceptable salts include thealkali metal, alkaline earth metal and ammonium salts, as well aspossibly salts with nontoxic inorganic and organic acids, for example,hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid,acetic acid, lactic acid, citric acid, malic acid, benzoic acid,salicylic acid, malonic acid, maleic acid, succinic acid ordiaminocapronic acid.

The salts are obtained in the usual manner, for example by neutraliisinga compound of general formula (I) with an appropriate base or acid.

For the preparation of pharmaceutical compositions, the compounds ofgeneral formula (I) are mixed in known manner with appropriatepharmaceutical carrier substances, aroma, flavouring and colouringmaterials, and formed, for example, into tablets or dragees or, with theaddition of appropriate adjuvants, suspended or dissolved in water or inan oil, for example olive oil.

The compounds of general formula (I) can be administered orally andparanterally in liquid or solid form. As injection medium, it ispreferred to use water which contains the stabilising agents,solubilising agents and/or buffers usual in the case of injectionsolutions. Such additives include, for example, tartrate and boratebuffers, ethanol, dimethyl sulphoxide, complex formers (such asethylenediaminetetraacetic acid), high molecular weight polymers (suchas liquid polyethylene oxide) for viscosity regulation or polyethylenederivatives of sorbitan anhydrides.

Solid carrier materials include, for example, starch, lactose, mannitol,methyl cellulose, talc, highly dispersed silicic acid and high molecularweight polymers (such as polyethylene glycols).

Compositions suitable for oral administration can, if desired, containflavouring and sweetening agents. For external application, thecompounds of general formula (I) according to the present invention canbe used in the form of powders or salves. For this purpose, they aremixed, for example, with powdered, physiologically compatible dilutionagents or conventional salve bases.

The dosage administered depends upon the age, the state of health andthe weight of the recipient, the extent of the disease, the nature offurther treatments carried out simultaneously, the frequency of thetreatment and the nature of the desired action. The daily dosage of theactive compound is usually from 0.1 to 50 mg./kg. body weight. Normally,0.5 to 40 and preferably 1.0 to 20 mg./kg./day in one or moreadministrations per day are effective in order to obtain the desiredresults.

Apart from the compounds mentioned hereinafter in the specific Examples,preferred compounds according to the present invention also include thefollowing:N-hydroxy-N-prop-2-enyl-S-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propyl]-3-thiopropionicacid amide,5-[S-(4-4-acetyl-3-hydroxy-2-propylohenoxy-butyl)-2-thioethyl]-(1H)-tetrazole;N-hydroxy-S-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)-butyl]-3-thiopropionicacid amidine.

The following Examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1N-Hydroxy-N-methyl-S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-thioacetamide.

2.6 g. (8 mMole)S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-propyl]-thioaceticacid are dissolved in 30 ml. methylene chloride, mixed with 0.81 g. (8mMole) 4-methylmorpholine and cooled to -10 to -15° C. 1.15 g. (8 mMole)isobutyl chloroformate in 10 ml. methylene chloride is added dropwise atthis temperature within the course of 10 minutes. Subsequently, thereaction mixture is further stirred for 15 minutes at the sametemperature and then mixed with 0.47 g. N-methylhydroxylamine in 10 ml.methylene chloride.

The reaction mixture is then stirred for 1 hour at -10° C. and for 2hours at 0° C. and subsequently warmed up to ambient temperature. Themethylene chloride is then stripped off and the residue boiled up twicewith ligroin. The residue thus obtained is dissolved in ethyl acetateand extracted three times with 2 M aqueous sodium hydroxide solution.The aqueous phase is acidified and extracted three times with diethylether. For removing unreacted starting material, the ethereal solutionis extracted three times with 2 M aqueous sodium carbonate solution. Theethereal solution is subsequently washed with water, 2 M hydrochloricacid and water, dried and evaporated. There is obtained 1.3 g. (46% oftheory) of the title compound in the form of an oil.

EXAMPLE 2

The following compounds are obtained in a manner analogous to thatdescribed in Example 1:

    ______________________________________                                                           Yield      m.p. (°C.)                               designation        %          (solvent)                                       ______________________________________                                        a   N-hydroxy-N-methyl-S-[3-(2-                                                                      60         oil                                             pentylphenoxy)-propyl]-3-                                                     thiopropionic acid amide                                                  b   N-hydroxy-N-methyl-S-[3-(3-                                                                      50         oil                                             pentylphenoxy)-propyl]-3-                                                     thiopropionic acid amide                                                  c   N-hydroxy-N-methyl-S-[4-(4-                                                                      71         oil                                             acetyl-3-hydroxy-2-propyl-                                                    phenoxy)-butyl]-3-thio-                                                       propionic acid amide                                                      d   N-hydroxy-N-methyl-S-[3-(4-                                                                      42         oil                                             acetyl-3-hydroxy-2-propyl-                                                    phenoxy)-propyl]-6-thio-                                                      hexanoic acid amide                                                       e   N-hydroxy-N-methyl-S-[4-(4-                                                                      30         oil                                             acetyl-3-hydroxy-2-allyl-                                                     phenoxy)-but-2-ynyl)-3-thio-                                                  propionic acid amide                                                      f   N-hydroxy-N-methyl-S-[4-(4-                                                                      70         oil                                             acetyl-3-hydroxy-2-propyl-                                                    phenoxy)-butyl]-thioacetamide                                             g   N-hydroxy-N-methyl-S-[4-                                                                         32         oil                                             (acetyl-3-hydroxy-2-propyl-                                                   phenoxy)-but-2-ynyl]-3-                                                       thiopropionic acid amide                                                  h   N-hydroxy-N-methyl-S-[3-(4-                                                                      35         oil                                             acetyl-3-hydroxy-2-allyl-                                                     phenoxy)-propyl]-3-thio-                                                      propionic acid amide                                                      i   N-hydroxy-N-methyl-S-[3-(4-                                                                      40         112-9                                           acetyl-3-hydroxy-2-propyl-    (ligroin/                                       phenoxy)-propyl]-3-thio-      diethyl                                         propionic acid amide          ether)                                      j   N-hydroxy-N-methyl-S-(3-                                                                         85         oil                                             phenoxypropyl)-3-thio-                                                        propionic acid amide                                                      k   N-hydroxy-N-methyl-S-[3-(3-                                                                      65         oil                                             methoxyphenoxy)-propyl]-3-                                                    thiopropionic acid amide                                                  l   N-hydroxy-N-methyl-S-[3-(3-                                                                      56         oil                                             {1-hydroxyhexyl}-phenoxy)-                                                    propyl]-4-thiobutyric acid                                                    amide                                                                     m   N-hydroxy-N-methyl-S-[3-(3-                                                                      65         oil                                             {1-hydroxyhexyl}-phenoxy)-2-                                                  hydroxypropyl]-4-thiobutyric                                                  acid amide                                                                n   N-hydroxy-N-methyl-S-[4-(3-                                                                      52         oil                                             {1-hydroxyhexyl}-phenoxy)-                                                    butyl]-3-thiopropionic acid                                                   amide                                                                     o   N-hydroxy-N-methyl-S-[4-(3-                                                                      15         oil                                             {1-hydroxyhexyl}-phenoxy)-                                                    but-2-enyl]-3-thiopropionic                                                   acid amide                                                                p   N-hydroxy-N-methyl-S-[3-(4-                                                                      47         oil                                             acetyl-3-hydroxy-2-propyl-                                                    phenoxy)-2-hydroxypropyl]-3-                                                  thiopropionic acid amide                                                  q   N-hydroxy-N-ethyl-S-[3-(4-                                                                       68         56                                              acetyl-3-hydroxy-2-propyl-    (ligroin)                                       phenoxy)-propyl]-3-thio-                                                      propionic acid amide                                                      r   N-hydroxy-N-propyl-S-[3-(4-                                                                      77         57-60                                           acetyl-3-hydroxy-2-propyl-    (ligroin)                                       phenoxy)-propyl]-3-thio-                                                      propionic acid amide                                                      s   N-hydroxy-N-phenyl-S-[3-(4-                                                                      70         64-66                                           acetyl-3-hydroxy-2-propyl-    (ligroin)                                       phenoxy)-propyl]-3-thio-                                                      propionic acid amide                                                      t   O-[S-(3-{4-acetyl-3-hydroxy-                                                                     14         oil                                             2-propylphenoxy}-propyl)-3-                                                   thiopropionyl]-cyclohexyl-                                                    hydroxylamine                                                             u   N-hydroxy-N-methyl-S-[5-(4-                                                                      31         76                                              acetyl-3-hydroxy-2-propyl-    (ligroin)                                       phenoxy)-pentyl]-3-thio-                                                      propionic acid amide                                                      v   N-hydroxy-N-methyl-S-[3-(3,4-                                                                    42         35-36                                           dichloro-2-propylphenoxy)-    (ligroin)                                       propyl]-3-thiopropionic acid                                                  amide                                                                     ______________________________________                                    

EXAMPLE 3N-[(1H)-Tetrazol-5-yl]-S-[3-(2-pentylphenoxy)-propyl]-3-thiopropionicacid amide.

0.9 g. (29 mMole) S-[3-(2-pentylphenoxy)-propyl]-3-thiopropionic acidare dissolved in 10 ml. methylene chloride and mixed with 0.29 g. (29mMole) N-methylmorpholine. The reaction mixture is cooled to -10° C. and0.39 g. (29 mMole) isobutyl chloroformate in 5 ml. methylene chlorideadded dropwise thereto at this temperature. The reaction mixture isfurther stirred for 15 minutes and thereafter a suspension of 0.3 g. (29mMole) 5-amino-(1H)-tetrazole in 5 ml. methylene chloride is addedthereto. Stirring is carried out for 1 hour at -10° C. and for 1.5 hoursat 0° C., whereafter the reaction mixture is allowed to warm up toambient temperature. The methylene chloride is then evaporated off andthe residue is mixed with ethyl acetate and extracted with 2 Mhydrochloric acid. The ethyl acetate phase is dried and evaporated.

After chromatography on silica gel using the system ligroin/ethylacetate (1:2 v/v) with 0.25% acetic acid, there is obtained 0.4 g. (37%of theory) of the title compound; m.p. 151-168° C.

EXAMPLE 4

The following compounds are obtained in a manner analogous to thatdescribed in Example 1:

    ______________________________________                                                             yield    m.p. (°C.)                               designation          %        (solvent)                                       ______________________________________                                        a     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     25       209                                               (4-acetyl-3-hydroxy-2-allyl-                                                                              (methanol)                                        phenoxy)-propyl]-3-thio-                                                      propionic acid amide                                                    b     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     40       190-3                                             (4-acetyl-3-hydroxy-2-propyl-                                                                             (ethyl                                            phenoxy)-propyl]-4-thio-    acetate)                                          hexanoic acid amide                                                     c     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     40       175-82                                            (3-{1-hydroxyhexyl}-phenoxy)-                                                                             (isoprop-                                         propyl]-4-thiobutyric acid  anol)                                             amide                                                                   d     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     50       164-7                                             (3-{1-hydroxyhexyl}-phenoxy)-                                                                             (diethyl                                          2-hydroxypropyl]-4-thio-    ether)                                            butyric acid amide                                                      e     N-[(1H)-tetrazol-4-yl]-S-[4-                                                                     36       148-50                                            (3-{1-hydroxyhexyl}-phenoxy)-                                                                             (water)                                           butyl]-3-thiopropionic acid                                                   amide                                                                   f     N-[(1H)-tetrazol-5-yl]-S-[4-                                                                     15       145-8                                             (3-{1-hydroxyhexyl}-phenoxy)-                                                                             (dichloro-                                        but-2-enyl]-3-thiopropionic methane/                                          acid amide                  methanol                                    g     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     45       165-7                                             (3,4-dichlorophenoxy)-propyl]-                                                                            (diethyl                                          3-thiopropionic acid amide  ether)                                      h     N-[(1H)-tetrazol-5-yl]-S-[4-                                                                     43       178-81                                            (4-acetyl-3-hydroxy-2-propyl-                                                                             (diethyl                                          phenoxy)-but-2-ynyl]-3-thio-                                                                              ether/                                            propionic acid amide        acetone)                                    i     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     55       160-62                                            (4-chlorophenoxy)-propyl]-3-                                                                              (water)                                           thiopropionic acid amide                                                j     N-[(1H)-tetrazol-5-yl]-S-[3-                                                                     68       174-76                                            (4-chloro-3-trifluoromethyl-                                                                              (iso-                                             phenoxy)-propyl]-3-thio-    propanol)                                         propionic acid amide                                                    ______________________________________                                    

EXAMPLE 55-{S-[3-(4-Acetyl-3-hydroxy-2-allylphenoxy)-propyl]-thiomethyl}-(1H)-tetrazole.

2.1 g. (7 mMole)S-[3-(4-acetyl-3-hydroxy-2-allylphenoxy)-propyl]-thioacetonitrile aredissolved in 50 ml. dimethylformamide, mixed with 2.27 g. (35 mMole)sodium azide and 1.87 g. (35 mMole) ammonium chloride and stirred for 48hours at 120° C. and 150 bar nitrogen.

The dimethylformamide is then evaporated off and the residue is mixedwith sodium hydroxide and filtered. The solution is shaken out withmethylene chloride, subsequently acidified and the product is extractedwith methylene chloride.

After chromatographing on silica gel with the system methylenechloride/methanol/water (325:225:25 v/v/v), there is obtained 0.6 g.(25% of theory) of the title compound; m.p. 129-132° C.

EXAMPLE 6

The following compounds are obtained in a manner analogous to thatdescribed in Example 5.

    ______________________________________                                                            yield    m.p. (°C.)                                designation         %        (solvent)                                        ______________________________________                                        a     4-{S-[3-(4-acetyl-3-hydroxy-                                                                    28       93                                                 2-propylphenoxy)-propyl]-5-                                                                              (dichloro-                                         thiopentyl}-(1H)-tetrazole methane/                                                                      methanol)                                    b     5-{S-[3-(4-acetyl-3-hydroxy-                                                                    41       126                                                2-propylphenoxy)-propyl]-2-                                                                              (dichloro-                                         thioethyl}-(1H)-tetrazole  methane/                                                                      methanol)                                    c     5-{S-[3-(2-pentylphenoxy)-                                                                      36       51                                                 propyl]-2-thioethyl}-(1H)- (ligroin)                                          tetrazole                                                               d     5-{S-[3-(4-acetyl-3-hydroxy-                                                                    32       112-9                                              2-allylphenoxy)-propyl]-2- (water)                                            thioethyl}-(1H)-tetrazole                                               ______________________________________                                    

EXAMPLE 7{S-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-thioethyl}-5-mercapto-(1H)-tetrazole.

0.7 g. (2 mMole)S-3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-2-thioethyl thiocyanateis dissolved in 25 ml dimethylformanide and mixed with 0.65 g. (10mMole) sodium azide and 0.53 g. (10 mMole) ammonium chloride in a steelautoclave. The mixture is allowed to react for 24 hours at 95° C. and150 bar nitrogen pressure. Subsequently, the dimethylformanide isdistilled off and the residue is mixed with 2 M aqueous sodium hydroxidesolution and extracted with ethyl acetate. The aqueous phase isacidified with 2 M hydrochloric acid and extracted with ethyl acetate.After evaporation, the residue is boiled with cyclohexane to give 0.22g. (28% of theory) of the title compound; m p. 96-97° C.

EXAMPLE 8

N-Hydroxy-S-[3-(2-pentylphenoxy)-propyl]-3-thiopropionic acid amide

2.08 g. (15 mMole) Hydroxylamine hydrochloride are dissolved in 30 ml.methanol and mixed with 45 ml. 1 M sodium methylate solution. After 30minutes, 4.87 g. methyl (15 mMole)S-3-(2-pentylphenoxy)-propyl-3-thiopropionate in 30 ml methanol areadded dropwise thereto and the reaction mixture is subsequently boiledunder reflux for 4 hours. Salt is removed by filtration and the filtrateis evaporated. The residue is then dissolved in ethyl acetate and thesolution further worked up as in Example 1. There are obtained 2.0 g.(41% of theory) of the title compound in the form of an oil.

EXAMPLE 9

The following compounds are obtained in a manner analogous to thatdescribed in Example 8:

    ______________________________________                                                             yield    m.p. (°C.)                               designation          %        (solvent)                                       ______________________________________                                        a     N-hydroxy-S-[3-(3-{1-hydroxy-                                                                    54       oil                                               hexyl}-phenoxy)-propyl]-4-                                                    thiobutyric acid amide                                                  b     N-hydroxy-S-[3-(3-{1-hydroxy-                                                                    36       oil                                               hexyl}-phenoxy)-2-hydroxy-                                                    propyl]-4-thiobutyric acid                                                    amide                                                                   c     N-hydroxy-S-[4-(3-{1-hydroxy-                                                                    20       oil                                               hexyl}-phenoxy)-butyl]-3-                                                     thiopropionic acid amide                                                d     N-hydroxy-S-[4-(3-{1-hydroxy-                                                                    41       oil                                               hexyl}-phenoxy)-but-2-enyl]-                                                  3-thiopropionic acid amide                                              e     N-hydroxy-S-[3-(3-pentyl-                                                                        32       oil                                               phenoxy)-propyl]-3-thio-                                                      propionic acid amide                                                    ______________________________________                                    

EXAMPLE 10S-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethanol

4.68 g. (60 mMole) 2-mercaptoethanol are stirred for 10 minutes atambient temperature with 60 ml. 1 M sodium methylate solution.Subsequently, 9.39 g. 3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propylbromide are added thereto and the reaction mixture is boiled underreflux for 5 hours. The reaction mixture is thereafter evaporated andthe residue mixed with water and ethyl acetate. The ethyl acetate phaseis successively shaken with 2 M aqueous sodium hydroxide solution andwith 2 M hydrochloric acid and then dried and evaporated. Afterrecrystallising the residue from diethyl ether/ligroin, there areobtained 6.4 g. (68% of theory) of the title compound; m.p. 72-74° C.

EXAMPLE 11S-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethylbromide

1.63 g. (5 mMole)S-3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethanol aredissolved in 15 ml. methylene chloride and mixed with 2.07 g. (6.25mMole) tetrabromomethane. The mixture is cooled to -10°C. and mixedportionwise with 1.96 g. (7.5 mMole) triphenyl phosphine. After stirringfor 15 minutes, the reaction mixture is mixed with diethyl ether and theprecipitate obtained is filtered off with suction. The diethyl ether isevaporated off and the residue is mixed with hexane. After filtering offthe precipitate and evaporating the hexane, there is obtained 1.7 g.(91% of theory) of the title compound; m.p. 74-75° C.

EXAMPLE 12S-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethylthiocyanate

1 0 g. (2.8 mMole)S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-mercaptoethylbromide and 5.0 g. potassium thiocyanate are heated to reflux for 2hours in 25 ml. acetone. Subsequently, the precipitate is filtered offwith suction, the solution is evaporated and the residue is stirred withdiethyl ether. After evaporating the diethyl ether, there is obtained0.7 g. (71% of theory) of the title compound in the form of an oil.

EXAMPLE 13S-[3-(4-Acetyl-3-hydroxy-2-allylphenoxy)-propyl]-3-mercaptopropionitrile

1.6 g. (6.3 mMole)3-(3-mercaptopropionitrile)-benzoisothiazole-S,S-dioxide is suspended in10 ml. acetonitrile under an atmosphere of nitrogen. 0.52 ml. piperidineis added thereto and the reaction mixture is stirred for 20 minutes atambient temperature. Subsequently, 0.92 g. DBU and 1.87 g. (6mMole)3-(4-acetyl-3-hydroxy-2-allylphenoxy)-propyl bromide are added theretoand the reaction mixture is stirred for 30 minutes at ambienttemperature. After evaporation, the residue is dissolved in ethylacetate, shaken with 2 M aqueous sodium hydroxide solution, washedneutral, dried and evaporated. After boiling with ligroin andevaporation, there is obtained 1.2 g. (63% of theory) of the titlecompound in the form of an oil.

EXAMPLE 14

The following compounds are obtained in a manner analogous to thatdescribed in Example 13:

    ______________________________________                                                             yield    m.p. (°C.)                               designation          %        (solvent)                                       ______________________________________                                        a     S-[3-(4-acetyl-3-hydroxy-2-                                                                      55       oil                                               propylphenoxy)-propyl]-6-                                                     thiohexane nitrile                                                      b     S-[3-(4-acetyl-3-hydroxy-2-                                                                      48       71                                                allyphenoxy)-propyl]-thio-  (ligroin)                                         acetonitrile                                                            c     S-[3-(4-acetyl-3-hydroxy-2-                                                                      49       42                                                propylphenoxy)-propyl]-3-   (dichloro-                                        thiopropionitrile           methane)                                    d     S-[3-(2-pentylphenoxy)-propyl]-                                                                  60       oil                                               3-thiopropionitrile                                                     ______________________________________                                    

EXAMPLE 15

Analogously to Example 2t but with the use of)-trimethylsilyl-cyclohexylhydroxylamine there is obtained the followingcompound:

    ______________________________________                                                            yield    m.p. (°C.)                                designation         %        (solvent)                                        ______________________________________                                        N-hydroxy-N-cyclohexyl-S-[3-(4-                                                                   36       124-5-                                           acetyl-3-hydroxy-2-propyl-   (ligroin/                                        phenoxy)-propyl]-3-thio-     acetone)                                         propionic acid amide                                                          ______________________________________                                    

The intermediates are prepared as follows:

a) [3-(1-Hydroxyhexyl)-phenoxymethyl-oxirane

19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 28.6 g. epichlorohydrinare dissolved in 25 ml. ethanol and heated to the boil. A solution of6.6 g. potassium hydroxide in 3 ml. water and 25 ml. ethanol is thenadded dropwise thereto in the course of 15 minutes. The reaction mixtureis boiled under reflux for 2 hours, the solvent is then distilled offand the residue is taken up in water. Extraction is carried out withethyl acetate, the ethyl acetate phase is washed twice with aqueoussodium hydroxide solution and water, dried and evaporated to give 22.4g. (89% of theory) of the title compound in the form of an oil.

b) 1-Bromo-3-[3-(1-hydroxyhexyl)-phenoxy]-propane

19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 80.4 g. (0.4 mole)dibromopropane are dissolved in 150 ml. methyl ethyl ketone and heatedto 80° C. 15.2 g. Potassium carbonate are added thereto in the course of1 hour. The reaction mixture is then stirred for 8 hours at 80° C., theresidue is filtered off and the solvent is evaporated, together withexcess dibromopropane. The residue is taken up in ethyl acetate,extracted twice with aqueous sodium hydroxide solution obtained 25.8 g.(82% of theory) of the title compound in the form of an oil.

c) The following compounds are obtained in a manner analogous to thatdescribed under b):

    ______________________________________                                                           yield      m.p. (°C.)                               designation        %          (solvent)                                       ______________________________________                                        1-bromo-4-[3-(1-hydroxyhexyl)-                                                                   89         oil                                             phenoxy]-butane                                                               1-chloro-4-[3-(1-hydroxyhexyl)-                                                                  85         oil                                             phenoxy]-but-2-ene                                                            ______________________________________                                    

d) EthylS-[3-(3-{1-hydroxyhexyl}-phenoxy)-2-hydroxypropyl]-4-mercaptobutyrate

9.42 g. (0.03 mole) ethylS-(benzoisothiazol-3-yl-1,1-dioxide)-4-mercaptobutyrate are dissolved in60 ml. acetonitrile. 2.5 ml. piperidine are added thereto under anatmosphere of nitrogen and the reaction mixture is stirred for 20minutes at ambient temperature. Subsequently, a solution of 5.52 g. DBUand 7.5 g. (0.03 mole) 3-(1-hydroxyhexyl)-phenoxymethyl-oxirane in 50 mlacetonitrile is added dropwise thereto. After 1 hour at ambienttemperature, the acetonitrile is distilled off and the residue is takenup in ethyl acetate, shaken out with 2 M aqueous sodium hydroxidesolution, washed neutral with water, dried and evaporated. The residueis stirred with diethyl ether, filtered off from insoluble material andevaporated. There are obtained 10.0 g. (84% of theory) of the titlecompound in the form of an oil.

e) The following compound is obtained in a manner analogous to thatdescribed under d):

    ______________________________________                                                           yield      m.p. (°C.)                               designation        %          (solvent)                                       ______________________________________                                        ethyl-S-[3-(3-{1-hydroxyhexyl}-                                                                  90         oil                                             phenoxy)-propyl]-4-mercapto-                                                  butyrate                                                                      ______________________________________                                    

f) S-[3-(3-{1-Hydroxyhexyl-phenoxy)-2-hydroxy-propyl]-4-mercaptobutyricacid

10.0 g. EthylS-[3-(3-{1-hydroxyhexyl}-phenoxy)-2-hydroxypropyl-4-mercaptobutyrate arestirred for 2 hours at 50° C. with 50 ml. methanol and 50 ml. 2 Maqueous sodium hydroxide solution. The solvent is subsequently strippedoff and the residue is taken up in water and extracted three times withethyl acetate. The aqueous phase is acidified with 2 M hydrochloric acidand extracted three times with ethyl acetate. The organic phase iswashed neutral, dried and evaporated. There are obtained 7.4 g. (80% oftheory) of the title compound in the form of an oil.

g) The following compound is obtained in a manner analogous to thatdescribed under f):

    ______________________________________                                                             yield    m.p. (°C.)                               designation          %        (solvent)                                       ______________________________________                                        S-[3-(3-{1-hydroxyhexyl}-phenoxy)-                                                                 85       oil                                             propyl]-4-mercaptobutyric acid                                                ______________________________________                                    

h) S-[4-(3-{1-Hydroxyhexyl}-phenoxy)-but-2-enyl]-3-mercaptopropionicacid

9.15 ml. (0.105 mole) 3-mercaptopropionic acid are dissolved in 70 ml.methanol and stirred with 315 ml. 1 M sodium methylate solution for 10minutes at ambient temperature under an atmosphere of nitrogen.Subsequently, 19.79 g. (0.07 mole)1-chloro-4-[3-(1-hydroxyhexyl)-phenoxy]-but-1-ene in 70 ml. methanol areadded dropwise thereto in the course of 15 minutes. The reaction mixtureis further stirred for 3 hours a ambient temperature and the solvent isthen stripped off. The residue is taken up in diethyl ether andextracted several times with 2 M aqueous sodium hydroxide solution. Theaqueous solution is acidified with 2 M hydrochloric acid and the desiredcompound is extracted with methylene chloride. After drying andstripping off the solvent, there are obtained 22.5 g. (91% of theory) ofthe title compound in the form of an oil.

i) The following compound is obtained in a manner analogous to thatdescribed under h):

    ______________________________________                                                             yield    m.p. (°C.)                               designation          %        (solvent)                                       ______________________________________                                        S-[4-(3-{1-hydroxyhexyl}-phenoxy)-                                                                 90       oil                                             butyl]-3-mercaptopropionic acid                                               ______________________________________                                    

Test Results for Pharmaceutical Activity

Activity of the inventive compounds was shown by the following testingin vitro. The testing shows inhibition of antigen-caused constriction ofpassively sensitized guinea pig pulmonary parenchyma strips in vitro(Organ Bath). For this study of the inventive compounds, a measurementwas made of the inhibition of the antigen-caused constriction ofpassively sensitized strips of guinea pig lung parenchyma, as describedherewith:

Pirbright-White guinea pigs were stunned by a blow to the neck and bled.The lungs were flushed largely free of blood in situ with Krebs' buffer,pH 7.4.

Then the lung was removed, cut into strips (approx. 20×4×4 mm) and thestrips were passively sensitized for one hour at room temperature with a1:50 dilution of a homologous anti-ovalbumin antiserum and then washedonce with Krebs' buffer.

The antiserum had previously been produced as described by Davies et al;(Quantitative studies on anaphylaxis in guinea pigs passively sensitizedwith homologous antibody. Inter. Arch Allergy 41, 648-654 (1971)) inguinea pigs of the same strain by the repeated injection of ovalbumin(2x crystallized) with the addition of complete Freund's adjuvant.

Until it was used, the antiserum was stored undiluted at -18° C.

Then the lung strips were suspended singly in 10-milliliter water bathswith a bias weight of 1.2 g on an isometric measuring receptable.

Then the baths were filled with Krebs' buffer and continually gassed at37° C. with O₂ (95%) and CO₂ (5%).

The constrictions of the lung strips were recorded through an amplifieron a plotter.

After a 30-minute habituating phase, histamine control spasms wereproduced in order to establish the reactivity of the lung specimens,washed, then the test substance was preincubated for 20 minutes at 37°C., and then the ovalbumin constriction was produced.

The inhibiting action of the compounds according to the invention wasexpressed as a percentage reduction of the constriction amplitude of the"specimens with the test substance" in proportion to the "untreatedcontrol constrictions."

                  TABLE                                                           ______________________________________                                        Inhibition of the antigen-induced constriction on the                         passively sensitized strip of pulmonary parenchyma (guinea                    pig)                                                                                 Inhibition (%)                                                         Substance                                                                              Superfusion     Organ Bath                                           from     Concentration                                                                             No. of  Concentration                                                                           No. of                                 Example No.                                                                            20 μM    Tests   5 μg/ml                                                                              Tests                                  ______________________________________                                        1        39          4                                                        2b       58          3                                                        2c       72          3                                                        2f       48          3                                                        2g                           67        4                                      2i       63          2       36        2                                      2l       44          3                                                        2m       29          3                                                        2n       33          4                                                        2o       42          4                                                        2t       15          4                                                        4c       29          3                                                        4d       83          3                                                        4e       73          3                                                        4f       26          3                                                        4g       75          2                                                        6a       70          3                                                        6b       55          3                                                        6c       13          6                                                        6d                           24        2                                      7        29          6                                                        9a       11          3                                                        9b       21          3                                                        9c       27          3                                                        ______________________________________                                    

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

What is claimed is:
 1. A compound of the formula: ##STR7## wherein Ar isphenyl, phenyl substituted one or more times by a radical selected fromthe group consisting of C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₁ -C₆ alkoxy, C₁-C₆ alkylthio, C₁ -C₄ alkanoyl, hydroxyl, hydroxy-C₁ -C₆ -alkyl,carboxyl, C₁ -C₆ alkoxycarbonyl, carbamoyl, nitro, amino or halogen,A isa straight-chained or branched, saturated or unsaturated C₁ -C₈aliphatic hydrocarbon which is unsubstituted or substituted by ahydroxyl group, n is 0, 1 or 2, B is a straight-chained or branched,saturated or unsaturated C₁ -C₈ -aliphatic hydrocarbon and R is5-(1H)-tetrazolyl, --CO--NH--tetrazolyl or -- (1H)--tetrazolylthio; or apharmacologically acceptable salt thereof.
 2. The compound of claim 1,wherein Ar is phenyl, phenyl substituted one or more times by a radicalselected from the group consisting of propyl, pentyl, allyl, methoxy,ethoxy, acetyl, hydroxyl, 1-hydroxyhexyl or halogen, A is methylene,ethylene, propylene, butylene, pentylene, but-2-enylene, but-2-ynyleneor 2-hydroxypropylene, n is 1, B is methylene, ethylene, propylene,butylene or pentylene, R is 5-(1H)-tetrazolyl, --CO--NH--tetrazolyl or5-(1H)-tetrazolylthio or a pharmacologically acceptable salt thereof. 3.The compound of claim 1, wherein Ar is phenyl substituted by a radicalselected from the group consisting of propyl, allyl, hydroxyl, acetyl,chloro or 1-hydroxyhexyl, A is propylene, butylene, but-2-enylene or2-hydroxy-propylene, n is 0, B is methylene, ethylene, propylene orpentylene and R is a 5-tetrazolylaminocarbonyl, 5-tetrazolyl or a5-tetrazolylthio or a pharmacologically acceptable salt thereof.
 4. Thecompound of claim 1 wherein Ar is 4-acetyl-3-hydroxy-2-propylphenyl,3-(1-hydroxyhexyl) phenyl or 3,4-dichlorophenyl; A is but-2-ynylene,propylene, or butylene or hydroxy substituted propylene; B is ethylene,propylene, or pentylene and R is [N-hydroxy-N-methylaminocarbonyl,]5-terazolylamino-carbonyl or 5-tetrazolyl, or a pharmaceuticallyacceptable salt thereof.
 5. The compound of claim 1 wherein R is5-tetrazolylaminocarbonyl or 5-tetrazolyl.
 6. The compound of claim 1wherein A is propylene, butylene, but-2-enylene, but-2-ynylene, or2-hydroxypropylene.
 7. The compound of claim 1 wherein B is ethylene,propylene or pentylene.
 8. The compound of claim 1 designatedN-[(1H)-tetrazol-5-yl]-S-[3-(3-{1-hydroxyhexyl}-phenoxy)-2-hydroxypropyl]-4-thio-butyricacid amide.
 9. The compound of claim 1 designatedN-[(1H)-tetrazol-5-yl]-S-[4-(3-{1-hydroxyhexyl}-phenoxy)-butyl]-3-thiopropionicacid amide.
 10. The compound of claim 1 designatedN-[(1H)-tetrazol-5-yl]-S-[3-(3,4-dichlorophenoxy)-propyl]-3-thiopropionicacid amide.
 11. The compound of claim 1 designated5-{S-3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl-5-thiopentyl}-(1H)-tetrazole.
 12. The compound of claim 1 wherein Ar is phenyl, phenylsubstituted one, two or three times and the substituents are selectedfrom the group consisting of C₁ -C₆ -alkyl, C₂ -C₆ -alkenyl, C₁ -C₆-alkoxy, C₁ -C₆ -alkylthio, C₁ -C₄ -alkanoyl, hydroxyl, hydroxy-C₁ -C₆-alkyl, carboxyl, C₁ -C₆ -alkoxy-carbonyl, carbamoyl, nitro, amino andhalogen.
 13. The compound of claim 1 designated5-{S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-thioethyl}-(1H)-tetrazole.14. The compound of claim 1 designated5-{S-[3-(4-acetyl-3-hydroxy-2-allylphenoxy)-propyl]-thiomethyl}-(1H)-tetrazole.15. A pharmaceutical composition for combating allergic diseasescontaining an effective amount to combat allergic diseases of thecompound of claim 1 in a pharmaceutically acceptable carrier.
 16. Thepharmaceutical composition of claim 15 wherein said compound is selectedform one or more of the group consisting of5-{S-[3-(4-acetyl-3-hydroxy-2-allylphenoxy)-propyl]-thiomethyl}1-(1H)-tetrazole;N-[(1H)-tetrazol-5-yl]-S-[3-(3,4-dichlorophenoxy)-propyl]-3-thiopropionicacid amide,5-{S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-5-thiopentyl}-(1H)-tetrazoleand5-{S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propyl]-2-thioethyl}-1(1H)-tetrazole.17. A method for combating allergic diseases in a patient suffering froman allergic disease comprising administering an effective amount tocombat said allergic disease, of the compound of claim 1 or apharmaceutically acceptable salt thereof.
 18. The method of claim 13wherein 0.1 to 50 mg/kg body weight is administered daily.
 19. A methodfor combating allergic diseases in a patient suffering from an allergicdisease comprising administering an effective amount to combat saidallergic disease, of the pharmaceutical composition of claim
 15. 20. Amethod for combating allergic diseases in a patient suffering from anallergic disease comprising administering an effective amount to combatsaid allergic disease of the pharmaceutical composition of claim 16.